Abstract
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by diverse cellular and biochemical aberrations, including decreased production of IL-2. Here we show that nuclear extracts from unstimulated SLE T cells, unlike extracts from normal T cells, express increased amounts of phosphorylated cAMP-responsive element modulator (p-CREM) that binds the -180 site of the IL-2 promoter. Nuclear extracts from stimulated normal T cells display increased binding of phosphorylated cAMP-responsive element binding protein (p-CREB) to the -180 site of the IL-2 promoter, whereas nuclear extracts from stimulated SLE T cells display primarily p-CREM and decreased p-CREB binding. In SLE T cells, p-CREM bound to the transcriptional coactivators, CREB binding protein and p300. Increased expression of p-CREM correlated with decreased production of IL-2. The transcription of a reporter gene driven by the -180 site was enhanced in normal T cells, but was suppressed in SLE T cells. These experiments demonstrate that transcriptional repression is responsible for the decreased production of IL-2 by SLE T cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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5' Untranslated Regions / metabolism
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Adult
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Aged
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CREB-Binding Protein
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Cyclic AMP Response Element Modulator
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Down-Regulation / genetics
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Down-Regulation / immunology
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Female
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Follow-Up Studies
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Humans
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Interleukin-2 / biosynthesis*
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Interleukin-2 / deficiency*
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Interleukin-2 / genetics
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Lupus Erythematosus, Systemic / drug therapy
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Lupus Erythematosus, Systemic / immunology*
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Lupus Erythematosus, Systemic / metabolism
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Macromolecular Substances
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Male
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Middle Aged
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Nuclear Proteins / metabolism
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Promoter Regions, Genetic / immunology
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Protein Binding / genetics
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Protein Binding / immunology
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Repressor Proteins / biosynthesis
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Repressor Proteins / metabolism
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Repressor Proteins / physiology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism*
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Trans-Activators / metabolism
Substances
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5' Untranslated Regions
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DNA-Binding Proteins
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Interleukin-2
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Macromolecular Substances
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Nuclear Proteins
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Repressor Proteins
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Trans-Activators
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Cyclic AMP Response Element Modulator
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CREB-Binding Protein
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CREBBP protein, human